Introduction. β-Caryophyllene (BCP) has been shown to be an effective anti-inflammatory agent in chronic and inflammatory pain models. Since limited data are available for BCP in acute pain, we tested efficacy of BCP in an acute post-surgical pain model. Methods. BCP was tested in an acute postsurgical pain model. Animals were treated with vehicle, 10, 25, 50 and 75 mg/kg BCP that was injected intra-peritoneally (i.p.). Time dependent paw withdrawal response (PWR) were evaluated using von Frey filaments and plasma and tissue samples were taken. BCP levels were determined in tissue (paw and spine) and plasma using an HPLC-MS based approach. Endocannabinoids (2-arachidonoylglycerol) were also evaluated in plasma and tissues using an HPLC-MS based approach. Monoacylglycerol lipase (MAGL) activity was evaluated in-vitro as well as ex vivo. Results. A dose-dependent improvement of hyperalgesia was observed up to 85% of the baseline value 30 minutes after administration of the highest BCP dose of 75 mg/kg. A BCP dose-dependent increase in the 2-arachidonoylglycerol (2-AG) levels was observed with 9.9 ± 6.4 ng/mL in the 75 mg/kg dose group as compared to vehicle controls with 3.0 ± 2.5 ng/mL. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC50 of 7.4 µM of BCP for MAGL inhibition. Conclusion. These data showed that BCP inhibits MAGL activity in-vitro and in-vivo causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose the 2-AG-mediated cannabinoid receptor activation may contribute to BCP’s mechanism of analgesia.